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MicroRNA-124-Targeted Zika Virus-A Dual-Functional Candidate as a Live-Attenuated Vaccine and Oncolytic Agent

ABSTRACT: Zika virus (ZIKV) poses a significant dual challenge: its profound neurotropism and neurovirulence are responsible for Congenital Zika Syndrome (CZS) and adult neuropathology, yet this neurotropism offers potential for oncolytic virotherapy against malignant brain tumors like glioma. However, the inherent safety risks of wild-type ZIKV constrain its clinical development as either a vaccine backbone or a therapeutic agent. In this study, we screened a microRNA, miR-124, which is highly enriched in neural cells, but low in glioma cells. Based on this finding, we engineered a recombinant ZIKV by inserting the miR‑124 target sequence (miR‑124T) into the genome, named ZIKV‑miR124T. A highly attenuated neurovirulence phenotype across multiple mouse models, including adult A129, BALB/c neonatal, and pregnant mice was identified for ZIKV-miR124T. Importantly, a single dose of ZIKV-miR124T provided complete protective immunity against lethal challenge for the immunized subject and effectively blocked vertical transmission, conferring protection to the fetus and neonate. Furthermore, in an orthotopic glioma model, ZIKV-miR124T maintained robust oncolytic efficacy while exhibiting a superior safety profile, demonstrated by viral replication being strictly confined to the tumor region and a nearly 1,000-fold reduction in non-tumoral brain viral load compared to a non-specific live-attenuated ZIKV (ZIKV-LAV). Overall, our study provides robust proof-of-concept for a rational, miRNA-targeting approach to develop a next-generation ZIKV candidate with dual potential as a safe live-attenuated vaccine and a precisely restricted oncolytic virus.

ORGANISM(S): Homo sapiens

PROVIDER: GSE331013 | GEO | 2026/05/14

REPOSITORIES: GEO

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